BAI1 localises AMPA receptors at the cochlear afferent postsynaptic density and is
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ABSTRACT:
PROVIDER: PRJNA1069109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27731200_1.fastq.gz | Fastqsanger.gz | |||
| SRR27731200_2.fastq.gz | Fastqsanger.gz | |||
| SRR27731201_1.fastq.gz | Fastqsanger.gz | |||
| SRR27731201_2.fastq.gz | Fastqsanger.gz | |||
| SRR27731202_1.fastq.gz | Fastqsanger.gz |
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Project description:Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming axo-somatic synapses with inner hair cells (IHCs), the primary sensory receptors of the mammalian cochlea. Although IHC ribbon synapses have been extensively studied, the molecular mechanisms regulating the structure and function of the post-synaptic density (PSD) at the SGN afferent terminals are largely unknown. Using functional, morphological, and transcriptomic approaches, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1), encoded by the Adgrb1 gene, is required for the clustering of the glutamate AMPA receptors GluR2-4 to the SGN post-synaptic density. Adult mice expressing BAI1 lacking the N-terminal thrombospondin type 1 repeats (TRS) have functional IHC synapses but fail to transmit acoustic information to the SGNs, leading to highly raised auditory thresholds. We also found that in adult Bai1-deficient mice, despite the almost complete absence of AMPA receptors, the SGN fibres innervating the IHCs did not degenerate. RNA sequencing and western blotting also indicate that AMPA receptors are expressed in the cochlea of Bai1-deficient mice, highlights that BAI1 is involved is trafficking or anchoring GluR2-4 to the PSDs. Moreover, these results have identified novel molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
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Project description:Deprivation of peripheral nerve input by cochlear removal in young mice results in dramatic neuron death in the cochlear nucleus (CN). The same manipulation in older mice does not result in significant loss. The molecular basis of this critical period of vulnerability remains largely unknown. Here we identified genes regulated at early time points after cochlear removal at ages when neurons are vulnerable (postnatal day (P)7) or invulnerable (P21) to this challenge. Afferent deprivation regulated very different sets of genes at P7 and P21. These genes showed a variety of functions at both ages, but surprisingly there was no net increase in pro-apoptotic genes at P7. A large set of upregulated immune-related genes was identified at P21. Experiment Overall Design: Mice received unilateral cochlear removals. At 6, 12, 24, and 48 hours after surgery, the CN ipsilateral and contralateral were removed, and RNA isolated from separate pools of tissue for each replicate. Deafferented CN were compared to age-matched and time-matched contralateral, control CN to identify genes regulated by cochlear removal at age P7 and P21.
2008-06-13 | E-GEOD-5394 | biostudies-arrayexpress
Project description:Deprivation of peripheral nerve input by cochlear removal in young mice results in dramatic neuron death in the cochlear nucleus (CN). The same manipulation in older mice does not result in significant loss. The molecular basis of this critical period of vulnerability remains largely unknown. Here we identified genes regulated at early time points after cochlear removal at ages when neurons are vulnerable (postnatal day (P)7) or invulnerable (P21) to this challenge. Afferent deprivation regulated very different sets of genes at P7 and P21. These genes showed a variety of functions at both ages, but surprisingly there was no net increase in pro-apoptotic genes at P7. A large set of upregulated immune-related genes was identified at P21. Keywords: Time Course after Cochlear Removal, Age Comparison
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Project description:The functional diversity of neuropeptides and/or their receptors may provide a complex means to modulate vestibular primary afferent neuronal function. The precise role of these neuropeptides in the physiology of the vestibular neuroepithelium is poorly understood. The vestibular caliceal afferent neurons when compared to the dimorphic and bouton afferent neurons have different functional properties. Immunofluorescent laser capture microdissection utilizing calretinin (calbindin 2, Calb2) antibodies allowed selective acquisition of these two primary afferent neuronal populations from the rat (Rattus norvegicus). After capturing the caliceal afferent neurons, as well as the dimorphic and bouton afferent neurons, microarray expression profiling was completed. Analysis of the resulting data revealed that there were 732 genes involved in synaptic/signaling, calcium binding/solute transport, and other. Of those genes, 52 were related to afferent modulation, including 21 genes representing neuropeptides or their receptors. The observed expression of 52 genes related to afferent modulation identified using microarray were confirmed using PCR from the Wackym-Soares normalized rat vestibular periphery cDNA library or by RT-PCR from fresh ganglia tissue. The majority of the neuropeptides and/or receptors were found to be expressed in both groups, although there were neuropeptides and/or receptors that were unique to the dimorphic and bouton afferent neuron pool. The expression of selected neuropeptides or their receptors was confirmed using immunohistochemistry in the crista ampullares. Our results suggest that the unexpected neuropeptide diversity and their differences in expression pattern could serve unique roles in the physiology of the vestibular neuroepithelium. Keywords: expression profiling, neuropeptides, vestibular neuroepithelium, calretinin
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Project description:Abstract: Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we utilize UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding for proteins known to interact with postsynaptic AMPA and NMDA receptors. Loci in/near Discs Large MAGUK Scaffold Protein 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P<5x10-8) for BF% and/or BMI. To further evaluate the functional role of PSD-95 (gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PDZ-domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising new therapeutic avenue for sustained weight loss.
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Project description:The cochlear nucleus is the first central pathway involved in the processing of peripheral auditory activity. It is heterogeneous in neuronal populations and physiologic responses and is organized in three major subdivisions: the anterior ventral cochlear nucleus (AVCN), the posterior ventral cochlear nucleus (PVCN) and the dorsal cochlear nucleus (DCN). Although each region demonstrates multiple cell types and functions, there are predominant populations of neurons in each region that underlie the principal role each subdivision plays in auditory processing. Little is known of the underlying genetic contribution to these properties. This study sought to identify genes expressed in the subdivisions of the cochlear nucleus that may account for the anatomical and physiological characteristics of each subdivision. These data provide a genetic basis for understanding normal auditory processing in the cochlear nucleus and a template for investigating changes that may occur with hearing loss, the generation and percept of tinnitus, and central processing disorders. Keywords: normal, comparative Brown Norway rats (n=40, female, 45days) were anesthetized and decapitated. Brains were rapidly removed and the subdivisions of the cochlear nucleus (AVCN, PVCN and DCN) dissected on dry ice. Total RNA was extracted and tested for concentration and purity by spectrophotometry and integrity by gel electrophoresis. SAGE was performed using the NlaIII enzyme and Invitrogen SAGE kit. Concatemers were commercially sequenced and imported into eSAGE (Margulies and Innis, 2000) for tag extraction and frequency.
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